DuoHexaBody-CD37 (GEN3009) is a bispecific antibody with a hexamerization-enhancing mutation that targets two different epitopes on CD37. DuoHexaBody-CD37 was designed to induce highly potent tumor cell kill in a variety of B-cell malignancies through enhanced complement-dependent cytotoxicity (CDC) and FcgR-mediated effector functions. Preclinical studies demonstrated promising anti-tumor activity in vitro, in vivo and ex vivo. DuoHexaBody-CD37 is being developed by Genmab and AbbVie. The clinical safety and preliminary anti-tumor activity of DuoHexaBody-CD37 are currently being explored in a first-in-human clinical trial in patients with B cell malignancies.

IgA is very potent in activating neutrophils to kill cancer cells. However, it has a short half-life since it does not bind to the neonatal Fc receptor, FcRn. With attaching an albumin binding domain (ABD) to IgA, the half-life can be substantially extended through binding of albumin.

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Novel ΔB7-H6-based immunoligands that bridge NKp30 on NK cells with EGFR on tumor cells were engineered by an evolutionary library approach combined with yeast display. Enhanced affinity for NKp30 significantly improved NK cell-mediated killing of tumor cells by up to 87-fold. Moreover, release of IFN-Δ and TNF-a was significantly increased. Affinity-matured ligands for NK cell-activating receptors may represent potent novel therapeutic agents with unique effector functions in cancer immunotherapy.

This talk will cover the rationale design of an immunocytokine platform for optimized bi-functional antagonist antibodies, how IL-7 can revives the cancer immunity cycle and reinvigorate exhausted T cells and human TILs, and how the 'In-cis delivery' of IL-7 to PD1+ T cells overcomes anti-PD1 resistance in immunocompetent or humanized mice models.

Antibody-cytokine fusions, capable of selective localization at the tumor site, may exhibit an increased therapeutic index, helping spare normal tissues. In this presentation, I will show examples on how antibody-cytokine fusions can be engineered to achieve potent anticancer activity and good selectivity. In particular, I will focus on products with activity-on-demand and on dual-cytokine fusions.

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Bispecific antibody discovery often takes the assumption that the best effective antibody as monoclonal will also be the best when transformed into the most optimal bispecific antibody. Showing an example I will show the undesired impact this assumption may have, I will emphasize the need for unbiased HT screening and discuss the impact of this on data management.

IgG mAbs eliminate tumor cells through NK cell-mediated ADCC and macrophage-mediated antibody-dependent phagocytosis. IgG, however, ineffectively recruits neutrophils as effector cells. By contrast, IgA mAbs induce neutrophil migration and activation through the IgA Fc receptor (FcaRI), but do not activate NK cells and have poorer half-life. We combined the agonistic activity of IgG mAbs and FcaRI targeting in a bispecific antibody, and results with this novel molecule will be discussed.

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Hemibodies are complementary fragments of a split T cell engaging device that acquire T cell recruiting competence after simultaneous binding to a target cell. Employing a pair of hemibodies addressing CD38 and SLAMF7, multiple myeloma cells are selectively eliminated, sparing CD38+ lymphocytes, hematopoietic stem and early progenitor populations from T cell mediated destruction. Thus, hemibodies enable combinatorial, ultra-high precision targeting of malignancies that are currently not accessibly by competing immunotherapeutics.

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We believe that the best candidates arise from drug geometry mimicking target geometry. While this can be hard to predict, empirical methods can identify these ideal candidates. We have developed an integrated antibody discovery and bispecific generation platform to create diverse panels of bispecific antibodies. By matrixing stable Fvs with different spatial geometries and valencies, we identify bispecific antibody candidates with required activity, specificity and developability.

Natural Killer (NK) cells can recognize and destroy cancer cells. NK cells also produce cytokines and chemokines that shape a multicellular immune response leading to a long lasting control of tumors. We have previously reported the generation of NK cell engagers (NKCEs), targeting two activating receptors, NKp46 and CD16, on NK cells and a tumor antigen on cancer cells. NKCEs were more potent in vitro than therapeutic antibodies targeting the same tumor antigen. They had similar pharmacokinetics to IgG1s and no off-target effects. We will present an update on NKCEs as a new generation of therapeutic molecules against cancer.

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